title: Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia.
abstract: BACKGROUND
  Methotrexate (MTX) is an important component of the therapy for childhood acute lymphoblastic leukemia. Treatment with high-dose MTX often causes toxicity, recommending a dose reduction and/or cessation of treatment. Polymorphisms in genes involved in the MTX metabolism have been associated with toxicity with controversial results. The discrepancies could be due to differences in treatment protocols among studies, small, or non-homogeneous populations or the use of different toxicity criteria. The aim of the present study was to analyze the possible correlation of polymorphisms of genes involved in the MTX metabolism with the toxicity during therapy with the well-established LAL/SHOP protocol.
  
  
  METHODS
  We analyzed 10 polymorphisms in seven genes (MTHFR, TS, SHMT1, RFC1, ABCB1, ABCG2, and SLCO1B1) from the MTX metabolism in 115 Spanish pediatric B-ALL patients, using MTX plasma concentration as an objective and quantifiable marker of toxicity.
  
  
  RESULTS
  We confirmed the suitability of MTX plasma levels as a toxicity marker. We found a statistically significant association between MTX plasma concentration and the SLCO1B1 rs11045879 CC genotype (P = 0.030). The rs4149081 AA genotype, in the same gene, could also be an indicator for high-MTX plasma concentrations. We did not find any significant association in the other genetic polymorphisms analyzed.
  
  
  CONCLUSIONS
  Identification of the rs4149081 and rs11045879 SLCO1B1 polymorphisms in children with ALL could be a useful tool for monitoring patients at risk of low-MTX clearance in order to avoid MTX-related toxicity.
authors.affiliation: Department of Genetics, Physic Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain.
authors.forename: Elixabet
authors.initials: E
authors.lastname: Lopez-Lopez
authors.forename: Idoia
authors.initials: I
authors.lastname: Martin-Guerrero
authors.forename: Javier
authors.initials: J
authors.lastname: Ballesteros
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Piñan
authors.forename: Purificacion
authors.initials: P
authors.lastname: Garcia-Miguel
authors.forename: Aurora
authors.initials: A
authors.lastname: Navajas
authors.forename: Africa
authors.initials: A
authors.lastname: Garcia-Orad
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000097:blood; D027361:Organic Anion Transporters / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D008727:Methotrexate